E-cadherin plays a critical role in many aspects of cell adhesion, epithelial development, and the establishment and maintenance of epithelial polarity. The loss of the adhesive function of ...E-cadherin is a critical step in the promotion of epithelial cells to a more malignant phenotype. We identified a C/A single nucleotide polymorphism at -160 from the transcriptional start site of the E-cadherin gene promoter. Transient transfection experiments showed that the A allele of this polymorphism decreased the transcriptional efficiency by 68% compared with the C allele (P<0.001). Electrophoretic mobility shift and footprinting assays revealed that the C allele had a stronger transcriptional factor binding strength than the A allele. These results indicate that the -160 C/A polymorphism has a direct effect on E-cadherin gene transcriptional regulation. This allelic variation may be a potential genetic marker that can help identify those individuals at higher risk for invasive/metastatic diseases.
Fibroblast Growth Factor 21 (FGF21) and Growth Differentiation Factor-15 (GDF-15) are putative neuroprotective cold stress hormones (CSHs) provoked by cold exposure that may be age-dependent. We ...sought to characterize serum FGF21 and GDF-15 levels in pediatric cardiac arrest (CA) patients and their association with use of therapeutic hypothermia (TH).
Secondary analysis of serum samples from clinical trials. We measured FGF21 and GDF-15 levels in pediatric patients post-CA and compared levels to both pediatric intensive care (PICU) and healthy controls. Post-CA, we compared normothermia (NT) vs TH (33 °C for 72 h) treated cohorts at < 24 h, 24 h, 48 h, 72 h, and examined the change in CSHs over 72 h. We also assessed association between hospital mortality and initial levels.
We assessed 144 samples from 68 patients (27 CA 14 TH, 13 NT, 9 PICU and 32 healthy controls). Median initial FGF21 levels were higher post-CA vs. healthy controls (392 vs. 40 pg/mL, respectively, P < 0.001). Median GDF-15 levels were higher post-CA vs. healthy controls (7,089 vs. 396 pg/mL, respectively, P < 0.001). In the CA group, the median change in FGF21 from PICU day 1–3 (after 72 h of temperature control), was higher in TH vs. NT (231 vs. –20 pg/mL, respectively, P < 0.05), with no difference in GDF-15 over time. Serum GDF-15 levels were higher in CA patients that died vs. survived (19,450 vs. 5,337 pg/mL, respectively, P < 0.05), whereas serum FGF21 levels were not associated with mortality.
Serum levels of FGF21 and GDF-15 increased after pediatric CA, and FGF21 appears to be augmented by TH.
To examine associations between household food insecurity and children's physical activity and sedentary behaviours.
Secondary analysis was conducted on the Healthy Communities Study, an ...observational study from 2013 to 2015. Household food insecurity was assessed by two items from the US Department of Agriculture's 18-item US Household Food Security Survey Module. Physical activity was measured using the 7-d Physical Activity Behaviour Recall instrument. Data were analysed using multilevel statistical modelling.
A total of 130 communities in the USA.
In sum, 5138 US children aged 4-15 years.
No associations were found for the relationship between household food insecurity and child physical activity. A significant interaction between household food insecurity and child sex for sedentary behaviours was observed (P = 0·03).
Additional research capturing a more detailed assessment of children's experiences of food insecurity in relation to physical activity is warranted. Future studies may consider adopting qualitative study designs or utilising food insecurity measures that specifically target child-level food insecurity. Subsequent research may also seek to further explore sub-group analyses by sex.
Pediatric robot-assisted laparoscopic (RAL) pyeloplasty has become a viable minimally invasive surgical option for ureteropelvic junction obstruction (UPJO) based on its efficacy and safety. However, ...RAL pyeloplasty in infants can be a challenging procedure because of the smaller working spaces. The use of the larger 8 mm instruments for these patients instead of the 5 mm instruments is common because of the shorter wrist lengths.
We hypothesized that the use of 5 mm instruments for RAL pyeloplasty in infants with smaller working spaces will have comparable perioperative parameters and surgical outcomes in comparison with older children with larger working spaces.
We compared the perioperative parameters and surgical outcomes of RAL pyeloplasties performed by a single surgeon in infants and non-infant pediatric patients over a 2 year period. All of the procedures were performed using an 8.5 mm camera and 5 mm robotic instruments. Patient demographics, operative times, perioperative complications, hospital pain medication usage, hospital length of stay, and treatment success rates were compared between the two groups.
A total of 65 pediatric RAL pyeloplasties were included in the study (16 infants and 49 non-infants, Table). There were no significant differences in gender, laterality, proportion of re-do pyeloplasty, or preoperative hydronephrosis grade between the two groups. All procedures were performed without conversion to open surgery or significant perioperative complications. There were no differences in segmental operative times (total operative time, console time, port placement time, time for dissection to UPJO, and anastomosis time), hospital pain medication usage, and hospital length of stay between the two groups (p > 0.05 for all comparisons). The treatment success rates were 93.8% (15/16) and 100% (49/49), respectively (p = 0.08).
We present the first comparative study of infant and non-infant pediatric RAL pyeloplasty using 5 mm robotic instruments. An advantage of the current study is the use of a single surgeon's experience to compare RAL pyeloplasty outcomes in infants with those of older children, a group in which RAL pyeloplasty has already been shown to be efficacious and safe. Operative tips for infant RAL pyeloplasty are also provided.
RAL pyeloplasty is a safe and effective surgical modality even in infants, with comparable perioperative parameters and outcomes as those in older children. The use of 5 mm instruments in infants does not affect outcomes and offers the potential for improved cosmesis.
Hypogammaglobulinemia (serum IgG levels < 7.0 g/L) has been associated with increased risk of COPD exacerbations but has not yet been shown to predict hospitalizations.
To determine the relationship ...between hypogammaglobulinemia and the risk of hospitalization in patients with COPD.
Serum IgG levels were measured on baseline samples from four COPD cohorts (n = 2,259): Azithromycin for Prevention of AECOPD (MACRO, n = 976); Simvastatin in the Prevention of AECOPD (STATCOPE, n = 653), Long-Term Oxygen Treatment Trial (LOTT, n = 354), and COPD Activity: Serotonin Transporter, Cytokines and Depression (CASCADE, n = 276). IgG levels were determined by immunonephelometry (MACRO; STATCOPE) or mass spectrometry (LOTT; CASCADE). The effect of hypogammaglobulinemia on COPD hospitalization risk was evaluated using cumulative incidence functions for this outcome and deaths (competing risk). Fine-Gray models were performed to obtain adjusted subdistribution hazard ratios (SHR) related to IgG levels for each study and then combined using a meta-analysis. Rates of COPD hospitalizations per person-year were compared according to IgG status.
The overall frequency of hypogammaglobulinemia was 28.4%. Higher incidence estimates of COPD hospitalizations were observed among participants with low IgG levels compared with those with normal levels (Gray's test, P < .001); pooled SHR (meta-analysis) was 1.29 (95% CI, 1.06-1.56, P = .01). Among patients with prior COPD admissions (n = 757), the pooled SHR increased to 1.58 (95% CI, 1.20-2.07, P < .01). The risk of COPD admissions, however, was similar between IgG groups in patients with no prior hospitalizations: pooled SHR = 1.15 (95% CI, 0.86-1.52, P =.34). The hypogammaglobulinemia group also showed significantly higher rates of COPD hospitalizations per person-year: 0.48 ± 2.01 vs 0.29 ± 0.83, P < .001.
Hypogammaglobulinemia is associated with a higher risk of COPD hospital admissions.
Platelet activation is a frontline response to injury, not only essential for clot formation but also important for tissue repair. Indeed, the reparative influence of platelets has long been ...exploited therapeutically where application of platelet concentrates expedites wound recovery. Despite this, the mechanisms of platelet-triggered cytoprotection are poorly understood. Here, we show that activated platelets accumulate in the brain to exceptionally high levels following injury and release factors that potently protect neurons from apoptosis. Kinomic microarray and subsequent kinase inhibitor studies showed that platelet-based neuroprotection relies upon paracrine activation of the epidermal growth factor receptor (EGFR) and downstream DNA-dependent protein kinase (DNA-PK). This same anti-apoptotic cascade stimulated by activated platelets also provided chemo-resistance to several cancer cell types. Surprisingly, deep proteomic profiling of the platelet releasate failed to identify any known EGFR ligand, indicating that activated platelets release an atypical activator of the EGFR. This study is the first to formally associate platelet activation to EGFR/DNA-PK--an endogenous cytoprotective cascade.
Colorectal cancer (CRC) is a leading cause of cancer-related deaths, with a 5% 5-year survival rate for metastatic disease, yet with limited therapeutic advancements due to insufficient understanding ...of and inability to accurately capture high-risk CRC patients who are most likely to recur. We aimed to improve high-risk classification by identifying biological pathways associated with outcome in adjuvant stage II/III CRC.
We included 1062 patients with stage III or high-risk stage II colon carcinoma from the prospective three-arm randomized phase 3 AVANT trial, and performed expression profiling to identify a prognostic signature. Data from validation cohort GSE39582, The Cancer Genome Atlas, and cell lines were used to further validate the prognostic biology. Our retrospective analysis of the adjuvant AVANT trial uncovered a prognostic signature capturing three biological functions-stromal, proliferative and immune-that outperformed the Consensus Molecular Subtypes (CMS) and recurrence prediction signatures like Oncotype Dx in an independent cohort. Importantly, within the immune component, high granzyme B (GZMB) expression had a significant prognostic impact while other individual T-effector genes were less or not prognostic. In addition, we found GZMB to be endogenously expressed in CMS2 tumor cells and to be prognostic in a T cell independent fashion. A limitation of our study is that these results, although robust and derived from a large dataset, still need to be clinically validated in a prospective study.
This work furthers our understanding of the underlying biology that propagates stage II/III CRC disease progression and provides scientific rationale for future high-risk stratification and targeted treatment evaluation in biomarker defined subpopulations of resectable high-risk CRC. Our results also shed light on an alternative GZMB source with context-specific implications on the disease's unique biology.
The risk of developing colorectal cancer in patients with chronic kidney disease (CKD) is twice that of the general population, but the factors associated with colorectal cancer are poorly ...understood. The aim of this study was to identify factors associated with advanced colorectal neoplasia in patients with CKD.
Prospective cohort study.
Patients with CKD stages 3-5, including those treated with maintenance dialysis or transplantation across 11 sites in Australia, New Zealand, Canada, and Spain, were screened for colorectal neoplasia using a fecal immunochemical test (FIT) as part of the Detecting Bowel Cancer in CKD (DETECT) Study.
Baseline characteristics for patients at the time of study enrollment were ascertained, including duration of CKD, comorbidities, and medications.
Advanced colorectal neoplasia was identified through a 2-step verification process with colonoscopy following positive FIT and 2-year clinical follow-up for all patients.
Potential factors associated with advanced colorectal neoplasia were explored using multivariable logistic regression. Sensitivity analyses were performed using grouped LASSO (least absolute shrinkage and selection operator) logistic regression.
Among 1,706 patients who received FIT-based screening—791 with CKD stages 3-5 not receiving kidney replacement therapy (KRT), 418 receiving dialysis, and 497 patients with a functioning kidney transplant—117 patients (6.9%) were detected to have advanced colorectal neoplasia (54 with CKD stages 3-5 without KRT, 34 receiving dialysis, and 29 transplant recipients), including 9 colorectal cancers. The factors found to be associated with advanced colorectal neoplasia included older age (OR per year older, 1.05 95% CI, 1.03-1.07, P<0.001), male sex (OR, 2.27 95% CI, 1.45-3.54, P<0.001), azathioprine use (OR, 2.99 95% CI, 1.40-6.37, P=0.005), and erythropoiesis-stimulating agent use (OR, 1.92 95% CI, 1.22-3.03, P=0.005). Grouped LASSO logistic regression revealed similar associations between these factors and advanced colorectal neoplasia.
Unmeasured confounding factors.
Older age, male sex, erythropoiesis-stimulating agents, and azathioprine were found to be significantly associated with advanced colorectal neoplasia in patients with CKD.
PDF
